Is CASP9 p.Pro338Ala (c.1012C>G) pathogenic?

CASP9 p.Pro338Ala (c.1012C>G) is classified Uncertain significance in CASP9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: likely benign (0.1028); Very rare (popmax 8.48e-05%, nfe).

How common is CASP9 p.Pro338Ala (c.1012C>G) in the general population?

CASP9 p.Pro338Ala (c.1012C>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CASP9 p.Pro338Ala (c.1012C>G)?

AlphaMissense predicts likely benign (score 0.1028) — an in-silico prediction, not a clinical call.

CASP9 p.Pro338Ala

c.1012C>G · VCV3995689

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1028 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1028	likely benign
REVEL	0.219	benign-leaning
SaProt	LLR 1.28	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 0.54, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 31 kb · p 0.1 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,388 alleles

Overall 6.85e-05% 1/1,460,606 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CASP9
Protein: p.Pro338Ala
Coding: c.1012C>G
MANE Select: NM_001229
Type: single nucleotide variant
Location: chr1:15495309 (GRCh38)
Gene constraint: LOEUF 0.994 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.86 · 13 PDB

Full CASP9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CASP9 c.720+9C>T Benign ★★ same type
CASP9 p.Ala28Val Benign ★★ same type
CASP9 p.Thr366Asn Benign ★★ ⚠ same type
CASP9 p.Ala141Val Uncertain significance ★ ⚠ same type
CASP9 p.Ala215Thr Uncertain significance ★ ⚠ same type
CASP9 p.Ala220Val Uncertain significance ★ ⚠ same type
CASP9 p.Ala226Ser Uncertain significance ★ ⚠ same type
CASP9 p.Ala28Thr Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/casp9-p-pro338ala (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown